Genital HSV-1 and HSV-2 infections continue to be among the most prevalent sexually transmitted infections worldwide. In US, the burden of genital HSV is reflected in recurrent genital herpes, neonatal herpes, and increased risk of HIV. In sub-Saharan Africa, HSV-2 is a principal driver of the HIV epidemic, especially among young women. Our research has focused on understanding the epidemiology, natural history and host-pathogen interactions in HSV-2 infection. We are proposing 4 Scientific Projects. Project 1 will test whether HSV-2 is the predominant cause of genital inflammation among Kenyan adolescents who will be followed from sexual debut to HSV-2 acquisition to test whether HSV-2 acquisition results in persistent enrichment of genital mucosa in HIV target cells. Project 2 will measure immunity in the blood and cervix of a well-defined cohort of HSV-2 infected participants, to test whether the magnitude, specificity, breadth, or phenotype of the systemic CD8 T-cell response to HSV-2 correlate with clinical or virologic severity in a cross-sectional cohort of immunocompetent women with chronic genital HSV-2 infection. In addition, we will determine the relationship at the TCR clonotype and peptide specificity levels between CD8 and CD4 T-cell responses in the blood in active lesions and in quiescent cervical and skin specimens. Project 3 will investigate the association between HSV-2 disease severity and the quantity, quality and diversity of tissue resident memory (TRM) CD8+ T cells at the site of previous HSV-2 reactivation, and whether the anatomic distribution, density, decay rate and the antiviral signature genes of TRM CD8+ T cells differ in subjects with mild versus severe herpes disease. It will also define whether the TCR repertoire dynamics and antigenic specificity of TRM CD8+ T cells are associated with disease outcomes. Project 4 will enroll participants with genital HSV-1 infection- now the most common cause of primary genital herpes in US - to determine the frequency of recurrences, and viral shedding among persons with genital HSV-1. In addition, we will test whether genital HSV-1 results in influx of inflammatory cells that is likly to increase the risk of HIV infection. Four supporting Cores are proposed: Clinical, Laboratory, Statistical and Administrative. Project 1 - Incident HSV-2 and Genital Health in Kenyan Adolescent Girls: An Inception Cohort (Description as provided by applicant) Herpes simplex virus type 2 (HSV-2) infections is one of the driving forces behind the HIV epidemic in sub-Saharan Africa. This is especially true for adolescent/young women who acquire both infections rapidly after sexual debut. We hypothesize that genital inflammation among young women in sub-Saharan Africa is largely driven by HSV-2 acquisition. Our Sp. Aim 1 will determine if HSV-2 acquisition among young African women results in persistent (>1 year) genital inflammation. The primary outcome will be the change in concentrations of the three pro-inflammatory factors MIP-1, IL-1, and IL-8, measured by Luminex assays in cervicovaginal lavage (CVL) samples from adolescent women before and after initiation of sexual activity, and after HSV-2 seroconversion. We will test for other sexually transmitted infections, and for sexual activity by PSA, to determine their relative contribution to genital inflammation. A secondary clinical outcome will be the density of vulvar infiltration with HIV target cells, as measured by absolute densities of CCR5+ T cells, macrophages and dendritic cells (DCs), quantified by immunofluorescence staining vulvar biopsies obtained from women before and after HSV-2 acquisition. We will compare these biopsies to matched control women who are sexually active but remain HSV-2 seronegative. In year 1 we will conduct an exploratory microarray transcriptome study in an ex vivo vulvovaginal explant tissue model of HSV-2 infection. Our Sp Aim 2 will test whether the frequency of HSV-2 reactivation at set point correlates with the degree of inflammatory changes. We will establish a cohort of HSV-2/HIV negative adolescent women in Thika, Kenya. The women who acquire HSV-2 infection will be enrolled into a 60-day intensive study of HSV-2 shedding, during which they self-collect daily genital swabs for HSV-2 detection. The results on this study will define the role of HSV-2 in mucosal priming of young women for HIV acquisition upon exposure, provide insights into the mechanism, and lay foundation for future interventions for HSV-2 such as chemoprophylaxis, microbicides or vaccines.